Cll Cell-Derived Exosomes Alter the Immune and Hematopoietic Systems

Authors

Ivo Veletic
David M Harris
Uri Rozovski
Maria Teresa S Bertilaccio
George A Calin
Koichi Takahashi
Ping Li
Zhiming Liu
Taghi Manshouri
Rares-Constantin Drula
Ken Furudate
Muharrem Muftuoglu
Anwar Hossain
William G Wierda
Michael J Keating
Zeev Estrov

Language

English

Publication Date

6-1-2025

Journal

Leukemia

DOI

10.1038/s41375-025-02590-x

PMID

40186065

PMCID

PMC12133404

PubMedCentral® Posted Date

12-1-2025

PubMedCentral® Full Text Version

Author MSS

Abstract

The origins of immunosuppression, neutropenia, and anemia in patients with chronic lymphocytic leukemia (CLL) are not fully understood. Because in patients with CLL, circulating exosomes, which participate in cell-to-cell interactions, are CLL cell-derived, we examined whether those exosomes contribute to abnormal features of this disease. Our data revealed that CLL cell-derived exosomes engulfed by healthy donors’ monocytes, fibrocytes, and lymphocytes altered target-cell gene and protein expression and suppressed normal hematopoiesis. CLL cell-derived exosomes increased normal monocytes’ CD14 and CD16 expression such that it mimicked the accessory cell profile and upregulated T cells’ checkpoint PD-1 and CD160 protein levels, potentially reducing T cell-mediated anti-CLL activity. In normal B cells, CLL cell-derived exosomes induced apoptosis and CD5 expression, suggesting that CLL cell-derived exosomes eliminate B cells and not all CD19+/CD5+ cells in CLL patients are clonal. RNA sequencing and quantitative real-time PCR revealed that CLL cell-derived exosomes harbored RNAs of pro-apoptotic genes and genes that increase metabolism, induce proliferation, and induce constitutive PI3K-mTOR pathway activation. CLL cell-derived exosomes inhibited hematopoietic progenitor proliferation, hindering the supportive effect of monocyte-derived fibrocytes. Together, our findings suggest that CLL cell-derived exosomes disrupt the immune and hematopoietic systems and contribute to disease progression in patients with CLL.

Keywords

Humans, Exosomes, Leukemia, Lymphocytic, Chronic, B-Cell, Hematopoiesis, B-Lymphocytes, Apoptosis, Monocytes

Published Open-Access

yes

Recommended Citation

Veletic, Ivo; Harris, David M; Rozovski, Uri; et al., "Cll Cell-Derived Exosomes Alter the Immune and Hematopoietic Systems" (2025). Faculty, Staff and Student Publications. 5349.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/5349